Chemically induced hepatocarcinogenesis in the adult rat will be used as a model to determine whether or not new hepatocyte phenotypes with altered proliferation control arise during the preneoplastic phase of liver neoplasia. Classes of hepatocytes will be chosen from suitable stages of hepatocarcinogenesis in donor animals. Specific in vitro phenotypes will be identified in single cells in primary cell cultures, and specific in vivo phenotypes identified following colony formation in vivo. Various hepatocyte phenotypes with altered proliferation control will be identified in vivo on the basis of their capability to form colonies in different host environments. Selection methods will be applied to the in vitro stage of this in vivo (donor) yields in vitro yields in vivo (host) sequence such that specific hepatocyte phenotypes (with specific capacities for proliferation control) may be recovered. This experimental system may provide a means to follow individual hepatocytes and their progeny through a progressive development of altered-proliferation-control properties until these cells are capable of colony formation in extrahepatic environments. To facilitate the study of hepatocyte lineages during hepatocarcinogenesis, specific chromosome markers will be developed. A study of the mechanism of "initiation" in the development of hepatocellular carcinoma will focus on the properties of a new hepatocyte phenotype that can be isolated at a preneoplastic stage and that may have properties in common with "initiated" hepatocytes. This phenotype can survive hepatocarcinogen toxicity in vitro, and the mechanism of this resistance will be investigated. The adaptation of in vivo systems suitable for the establishment of specific levels of altered proliferation control in hepatocytes of other species may provide new approaches for the development of diagnostic procedures for preneoplasia in humans.